Patients with essential hypertension (HTs) have impaired endothelial nitric oxide (NO) activity. Although its mechanism is unknown, we have previously shown that the abnormality is not localized at the receptor or the G protein level. To investigate whether the endothelial dysfunction of HTs is related to a more distal defect in intracellular signal transduction, we studied the forearm blood flow response to intraarterial infusion of isoproterenol (ISO; 50-200 ng/min), a beta2 agonist that stimulates NO release through the Gs protein/cAMP pathway, and acetylcholine (Ach; 7.5-30 microg/min), an endothelial agonist that acts through the Gi/o/phosphoinositol pathway, in 12 normotensives (NTs) and 12 HTs. The infusion of ISO was repeated during the concurrent infusion of L-NMMA (4 micromol/min), a blocker of NO synthesis. The vasodilator response to ACh was significantly reduced in HTs compared to NTs (maximum flow: 10.4+/-4.6 vs. 14.4+/-3.7 mL/min/dL; P=0.008). However, the vasodilator effect of ISO was similar in NTs and HTs (maximum flow: 14.4+/-5.4 vs 13.5+/-5 mL/min/dL; P=0.56), and was significantly and equally blunted by L-NMMA in both groups (22+/-15% in NTs vs 23+/-16% in HTs; P=0.83). The vasodilator response to sodium nitroprusside (0.8-3.2 microg/min), an exogenous NO donor, was similar in both groups and not modified by L-NMMA. Thus, in HTs with impaired endothelium-dependent vasodilation to ACh, the NO release in response to beta2- adrenergic stimulation is preserved. These findings suggest that the endothelial abnormality in hypertension is at least partly related to a defect in the phosphoinositol pathway.